IBX as a catalyst for dehydration of hydroperoxides: Green entry to α,β-unsaturated ketones: Via oxygenative allylic transposition

Article abstract of DOI:10.1039/c7cc08957k

A catalytic transformation of allylic hydroperoxides into α,β-unsaturated carbonyl compounds using IBX as a dehydration catalyst is described. The combination of a singlet oxygen ene reaction and the IBX-catalyzed dehydration provides α,β-unsaturated carbonyl compounds from alkenes via oxygenative allylic transposition with H₂O as the only byproduct.

Full text of DOI:10.1039/c7cc08957k

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IBX as a Catalyst for Dehydration of Hydroperoxides: Green Entry
a b
to , -Unsaturated Ketones via Oxygenative Allylic Transposition
Tetsuya Kuga, Yusuke Sasano and Yoshiharu Iwabuchi*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A catalytic transformation of allylic hydroperoxides into
unsaturated carbonyl compounds using IBX as a dehydration a paucity of methods for Type II allylic oxygenations to furnish
catalyst is described. The combination of a singlet oxygen ene either allylic alcohols or -unsaturated carbonyl compounds.
reaction and the IBX-catalyzed dehydration provides For the latter transformation, only the protocol by Mihelich and
a
,
b
-
strategy in organic synthesis. On the other hand, there has been
a,b
, -
a b
unsaturated carbonyl compounds from alkenes via oxygenative coworkers, consisting of a sequential singlet oxygen ene
reaction (Schenck ene reaction)5b,6 with an alkene and the
allylic transposition with H2O as the only byproduct.
following acetylation–dehydroacetoxylation of the allylic
hydroperoxide, has been shown for Type II allylic oxygenation
Green and sustainable transformations are of increasing
importance in recent years,1 which particularly spurred the
pursuit of catalytic methods that realize direct and efficient C–
H functionalization.2 Because of the ready accessibility of the
substrate as well as the versatile uses of the product, the allyic
to obtain the corresponding
a,b-unsaturated carbonyl
compounds (Scheme 2).7,8 Although Mihelich’s protocol has
been applied to the synthesis of complex molecules,9 several
drawbacks remain to be addressed: the dehydration of
C–H oxygenation of an alkene to give an allylic alcohol or a,b-
hydroperoxide
5 into a,b-unsaturated carbonyl compound 4
unsaturated carbonyl compound has been a rewarding subject
does not proceed under mild conditions, thus requiring the use
of a stoichiometric activating reagent such as Ac2O to promote
this reaction by generating extremely reactive acetyl
alkylperoxide 6, which potentially suffers from thermal runaway.
The use of a stoichiometric activating reagent results in the
generation of stoichiometric organic wastes.
in synthetic organic chemistry.3
Two logical pathways have arisen from the C–H oxygenation of
an alkene with an unsymmetrical allylic motif (Scheme 1): the
direct oxygenation at the allylic position of alkene
(Type I),3,4 and oxygenation involving the migration of alkene
to give
(Type II).5
1
to give
2
1
3
A number of useful methods to conduct Type I allylic
oxygenation have been developed, constituting a reliable
Scheme 2 Type II allylic oxygenation of alkenes into enones
Considering the homology to the Kornblum–DeLaMare
reaction of dialkyl peroxide, which proceeds under relatively
mild conditions including catalytic processes,10 we envisaged
the development of a catalytic transformation of allylic
Scheme 1 Pathways of oxygenation of unsynmmetrical alkenes
hydroperoxides to give
(Scheme 3). Herein, we report the first organocatalytic
transformation of allylic hydroperoxides to give a,b-
a,b-unsaturated carbonyl compounds
unsaturated carbonyl compounds using the hypervalent iodine
reagent IBX. We also demonstrate that the IBX catalysis enabled
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Table 1 Optimization of reaction conditionsa
a one-operation process of the Schenck ene reaction and
concomitant fragmentation of the primarily generated allylic
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DOI: 10.1039/C7CC08957K
hydroperoxides to give
via a Type II reaction.
a,b-unsaturated carbonyl compounds
entry catalyst
solvent additive
yieldb
(%)
Trace
7
12
11
1
(F3C)2C=O
AZADO+BF4
PhI(OAc)2
PhIO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-
2
3
4
Scheme 3 Fragmentation of alkyl peroxides
5
6
7
8
PhI(OH)OTs CH2Cl2c
dec.
37
12
59
68
IBA
CH2Cl2
CH2Cl2c
CH2Cl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
First, we explored basic or acidic catalysts that are used in a
typical Kornblum–DeLaMare reaction to convert an allylic
DMP
IBX
IBX
IBX
IBX
IBX
IBX
IBX-OTs
hydroperoxide into an
a,b-unsaturated carbonyl compound.
9
However, these catalysts did not promote the reaction well (see
ESI), prompting us to explore an alternative strategy to achieve
this transformation (Scheme 4). We conceived that an
electrophilic covalent catalysis would achieve the
10
11
12
13f
14
15
TFAd
83
(PhO)2P(O)OHd 77
p-TsOH·H2Oe
p-TsOH·H2O
83 (4 h)
70
68 (6 h)
0
transformation of allylic hydroperoxides to give
unsaturated carbonyl compounds.11 A hydroperoxide and an
electrophile would react to provide a covalent intermediate
Then would collapse into an enone ( ) and a hydrate ( ), via a
a,b-
p-TsOH·H2Oe
7
.
aAll reactions were carried out with 0.2 mmol of 5a in 1 mL of CH2Cl2 or 0.4 mL of DMSO.
7
4
9
bDetermined by 1H-NMR analysis using mesitylene as an internal standard. c 5% DMSO
proton transfer and O–O bond cleavage. Finally, the catalyst
would regenerate by dehydration.
-
was added. d 20 mol% e 10 mol% f 5 mol% IBX and p-TsOH·H2O were used. AZADO+BF4
=
2-azaadamantane N-oxoammonuim tetrafluoroborate, IBA = 2-iodosobenzoic acid,
DMP = Dess–Martin periodinane, IBX = 2-iodoxybenzoic acid, TFA = trifluoroacetic acid,
p-TsOH = p-toluenesulfonic acid, IBX-OTs = 2-iodoxybenzoic acid tosylate.
With the optimal conditions determined, we evaluated the
scope of the substrate (Scheme 5). These conditions tolerated
various functional groups including esters (4b–e), a nitrile (4c),
a phthalimide (4d), an amide (4f), and a silyl ether (4n). The
bulky substrate prolonged the reaction, but the resulting enone
was obtained in good yield (4g). The hydroperoxides obtained
from cyclic alkenes gave corresponding cyclic enones in
moderate to good yield (4i–n). Cyclopentenone 4j, which is the
key intermediate in the synthesis of natural products or the
ligand of organometallic complexes, was obtained in reasonable
Scheme 4 Working hypothesis
We screened electrophiles for the catalytic transformation of
2-cyclohexene-1-hydroperoxide (5a) into 2-cyclohexene-1-one
(
4a) (Table 1). Although treatment of hydroperoxide 5a with
several classes of electrophiles at room temperature for 12 h
resulted in almost no reaction (entries 1, 2), the use of PhI(OAc)2
provided the desired enone in low yield (entry 3).12,13 Then, we
compared the reactivity of hypervalent iodine catalysts (entries
3–8). In the case of IBA and IBX, small amount of DMSO was
added to dissolve the catalysts (entries 6 and 8). We found that
IBX was the optimal electrophilic catalyst for this reaction (entry
8). We consider that higher electrophilicity of IBX compared to
iodine(III) reagents realized the efficient catalytic reaction. The
condition using DMP in CH2Cl2 generated insoluble solid, which
was estimated as IBX, and thus the reaction stopped at low
conversion (entry 7). The use of DMSO as the sole solvent under
more concentrated conditions gave higher yield of 4a (entry 9).
Next, we examined several acidic additives to promote the
reaction (entries 10-12).14 Eventually, p-TsOH was identified as
the best acid catalyst to complete this reaction within 4 h and
enone 4a was obtained in good yield (entry 12). Decreasing the
catalytic amount prolonged the reaction (entry 13). IBX-OTs15
showed a similar reactivity to a combination of IBX and p-TsOH,
but slight decomposition was observed (entry 14). The reaction
did not proceed in the absence of IBX (entry 15).
Scheme 5 Substrate scope a Isolated as a 2,4-dinitrophenylhydrazone.
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yield.16 The primary hydroperoxide was also applicable to this
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reaction to give the -unsaturated aldehyde 4m.
a
,
b
Unfortunately, the acetal-protected substrate decomposed to
give enone 4o in low yield.
Encouraged by the promising results, we investigated a one-
operation process of the singlet oxygen ene reaction and
concomitant IBX-catalyzed transformation of an allylic
hydroperoxide into an
a,b
-unsaturated carbonyl compound.17
This method would provide a solution to the problems of
handling the potentially explosive allylic hydroperoxide. It is
noted that singlet oxygen has to be generated in the presence
of photosensitizers, which are often deactivated by oxidants
such as IBX. We screened the photosensitizers under O2
atmosphere with irradiation by a household fluorescent lamp to
avoid the use of special equipment. As a result, it was found that
C
60 is the suitable photosensitizer to give enone 4k in good yield
(Scheme 6).18,19 This method gave various cyclic enones
including cyclopentenones (4p 4i), cyclohexenones (4q 4r),
Fig. 1 Monitoring of reaction mixture a Determined by 1H-NMR analysis using
mesitylene as an internal standard.
,
,
cycloheptenones (4s–u), and cyclooctenone 4v. Cyclohexenes
1q and 1r, and cyclooctene 1v reacted with singlet oxygen
slowly; corresponding enones were obtained in low yield after
24 h with the recovered alkenes. Heterocyclic alkene was also
applicable to give enone 4w. Acyclic enone 4h was obtained in
moderate yield under these conditions because of the low
To gain insight into the mechanism of the IBX-catalyzed
dehydration, we carried out some experiments and calculations
below (see the ESI for details): (i) 18O-labelling experiments
indicated that the oxygen atom of the enone products should
come from molecular oxygen (Scheme 7a). (ii) to evaluate the
selectivity of a singlet oxygen ene reaction of a trisubstituted feasibility of the mechanism in Scheme 4, the activation energy
alkene.
of the proton transfer and O–O bond cleavage step was
estimated by DFT calculations. Although a six-membered
transition state (cf.
kcal/mol), ten-membered (or linear) transition state
7
) gave a high activation energy (ΔG‡ = 31.7
a
incorporating a DMSO molecule gave a reasonable activation
energy (ΔG‡ = 23.7 kcal/mol). Based on the above results, we
propose a possible reaction mechanism (Scheme 7-b). An allylic
hydroperoxide, generated by a singlet oxygen ene reaction of
an alkene (
1), would reacts with IBX to form an adduct (7’),
which would collapse with the deprotonation by a DMSO (or
another basic) molecule to afford an enone (4).
Scheme
6 a 2,4-
Scope of the one-operation reaction aIsolated as
dinitrophenylhydrazone.
Next, we confirmed the safety of this one-operation process.
Monitoring of the reaction mixture by 1H-NMR clearly indicated
that a low concentration of allylic hydroperoxide 5k existed (Fig.
1). Thus, this method would provide a solution to the handling
of the potentially explosive intermediate. Note that we consider
hydroperoxide 5k was the reliable intermediate of this one-
operation process on the basis of the experiments shown
below: (i) almost no reaction was observed when DABCO, which
is known to quench singlet oxygen,20 was added; (ii)
hydroperoxide 5k was obtained in the absence of IBX; (iii)
trapping experiment of singlet oxygen using 9,10-
dimethylanthracene suggested that singlet oxygen was
generated under these one-operation reaction conditions; (iv)
no reaction was observed in dark (see section 4 in the ESI).
Scheme 7. Mechanistic Investigation
In conclusion, we have developed a method of catalytic
transformation of allylic hydroperoxides into -unsaturated
carbonyl compounds, which are easily prepared by an ene
a,b
reaction of singlet oxygen and alkenes, using IBX and p-TsOH as
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P. H. Dussault, Tetrahedron Lett. 2010, 51, 5615; (c) C. He, J.
the catalysts. This reaction is the first example of not only the
catalytic transformation of hydroperoxides into enones, but
also the use of a hypervalent iodine catalyst other than in
oxidation reaction. The combination of singlet oxygen ene
reaction and this method enables oxygenative allylic
transposition of alkenes into enones with water as the only
stoichiometric waste. This reaction was applicable to the one-
operation conversion of alkenes to enones. Further studiess to
increase the efficiency of the one-operation reaction and to gain
the insight into the mechanism are under way.
This work was partly supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysis” (No. 23105011) from
MEXT, “Precisely Designed Catalysts with Customized
Scaffolding” (No. JP16H00998) from JSPS, and Life Science
Research (Platform for Drug Discovery, Informatics, and
Structural Life Science) from Japan Agency for Medical Research
and Development (AMED), Japan.
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Hu, Y. Wu and H. Ding, J. Am. Chem. Soc. 2017, 139, 6098.
DOI: 10.1039/C7CC08957K
8
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Conflicts of interest
There are no conflicts to declare.
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